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Singlet fission is a carrier multiplication mechanism that could make silicon solar cells much more efficient. The singlet-fission process splits one high-energy spin-singlet exciton into two lower-energy spin-triplet excitons. We calculated the efficiency potential of three technologically relevant singlet-fission silicon solar cell implementations. We assume realistic but optimistic parameters for the singlet-fission material and investigate the effect of singlet energy and entropic gain. If the transfer of triplet excitons occurs via charge transfer, the maximum efficiency is 34.6% at a surprisingly small singlet energy of 1.85 eV. For the Dexter-type triplet energy transfer, the maximum efficiency is 32.9% at a singlet energy of 2.15 eV. For Förster resonance energy transfer (FRET), the triplet excitons are first transferred into a quantum dot, from which they then undergo FRET into silicon. For this transfer mechanism, the maximum efficiency is 28.% at a singlet energy of 2.33 eV. We show that the efficiency gain from singlet fission is larger the more efficient the silicon base cell is, which stands in contrast to tandem perovskite–silicon solar cells.

Superoxide formation is a hallmark of cardiovascular disease with the involvement of different tissues and cell types. Identification of the cellular sources and subcellular localization of superoxide formation is important to understand the underlying disease pathomechanisms. In the present study, we used HPLC quantification of the superoxide-specific oxidation products of hydroethidine (HE or DHE) and its derivative hydropropidine (HPr+) for measurement of intra- and extracellular superoxide formation in isolated leukocytes and tissues of hypertensive rats. Superoxide generation by isolated leukocytes from human subjects as well as tissue samples of hypertensive rats (infusion of angiotensin-II for 7 days) was investigated using HPr+ and HE fluorescent probes with HPLC or plate reader detection. Both fluorescent dyes were used to test for intra- and extracellular superoxide formation using the supernatant or cell/tissue pellet for analysis. We demonstrate the correlation of impaired functional parameters (blood pressure, vascular function, and oxidative burst) and increased superoxide formation in different organ systems of hypertensive rats using the HPr+/HPLC method. In the cell model, the differences between HE and HPr+ and especially the advantage of the extracellular specificity of HPr+, due to its cell impermeability, became evident. Plate reader-based assays showed much higher background signal and were inferior to HPLC based methods. In conclusion, the HPr+/HPLC assay for superoxide determination is highly reliable in isolated immune cells and an animal model of arterial hypertension. In particular, the cell impermeability of HPr+ made it possible to differentiate between intra- and extracellular superoxide formation.

Background and Purpose Organic nitrates such as nitroglycerin (NTG) or pentaerythritol tetranitrate (PETN) have been used for over a century in the treatment of angina or ischaemic heart disease. These compounds are prodrugs which release their nitrovasodilators upon enzymic bioactivation by aldehyde dehydrogenase (ALDH2) or cytochromes P450 (CYP). Whereas ALDH2 is known to directly activate organic nitrates in vessels, the contribution of vascular CYPs is unknown and was studied here. Experimental Approach As all CYPs depend on cytochrome P450 reductase (POR) as electron donor, we generated a smooth muscle cell-specific, inducible knockout mouse of POR (smcPOR−/−) to investigate the contribution of POR/CYP to vascular biotransformation of organic nitrates. Key Results Microsomes containing recombinant CYPs expressed in human vascular tissues released nitrite from NTG and PETN with CYP2C9 and CYP2C8 being most efficient. SFK525, a CYP suicide inhibitor, blocked this effect. smcPOR−/− mice exhibited no obvious cardiovascular phenotype (normal cardiac weight and endothelium-dependent relaxation) and plasma and vascular nitrite production was similar to control (CTL) animals. NTG- and PETN-induced relaxation of isolated endothelium-intact or endothelium-denuded vessels were identical between CTL and smcPOR−/−. Likewise, nitrite release from organic nitrates in aortic rings was not affected by deletion of POR in smooth muscle cells (SMCs). In contrast, inhibition of ALDH2 by benomyl (10 μM) inhibited NTG-induced nitrite production and relaxation. Deletion of POR did not modulate this response. Conclusions and Implications Our data suggest that metabolism by vascular CYPs does not contribute to the pharmacological function of organic nitrates.

Background: Large epidemiological studies point towards a link between the incidence of arterial hypertension, ischaemic heart disease, metabolic disease and exposure to traffic noise, supporting t...

Ischemia/reperfusion (I/R) events are involved in the pathophysiology of numerous ocular diseases. The purpose of this study was to test the hypothesis that betulinic acid protects from I/R injury in the mouse retina. Ocular ischemia was induced in mice by increasing intraocular pressure (IOP) to 110 mm Hg for 45 min, while the fellow eye served as a control. One group of mice received betulinic acid (50 mg/kg/day p.o. once daily) and the other group received the vehicle solution only. Eight days after the I/R event, the animals were killed and the retinal wholemounts and optic nerve cross-sections were prepared and stained with cresyl blue or toluidine blue, respectively, to count cells in the ganglion cell layer (GCL) of the retina and axons in the optic nerve. Retinal arteriole responses were measured in isolated retinas by video microscopy. The levels of reactive oxygen species (ROS) were assessed in retinal cryosections and redox gene expression was determined in isolated retinas by quantitative PCR. I/R markedly reduced cell number in the GCL and axon number in the optic nerve of the vehicle-treated mice. In contrast, only a negligible reduction in cell and axon number was observed following I/R in the betulinic acid-treated mice. Endothelial function was markedly reduced and ROS levels were increased in retinal arterioles of vehicle-exposed eyes following I/R, whereas betulinic acid partially prevented vascular endothelial dysfunction and ROS formation. Moreover, betulinic acid boosted mRNA expression for the antioxidant enzymes SOD3 and HO-1 following I/R. Our data provide evidence that betulinic acid protects from I/R injury in the mouse retina. Improvement of vascular endothelial function and the reduction in ROS levels appear to contribute to the neuroprotective effect.

Oral treatment of apolipoprotein E-knockout (ApoE-KO) mice with the putative sirtuin 1 (SIRT1) activator resveratrol led to a reduction of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in the heart. In contrast, the SIRT1 inhibitor EX527 enhanced the superoxide production in isolated human polymorphonuclear granulocytes. In human monocytic THP-1 cells, phorbol ester-stimulated superoxide production was enhanced by inhibitors of histone deacetylases (HDACs; including quisinostat, trichostatin A (TSA), PCI34051, and tubastatin A) and decreased by inhibitors of histone acetyltransferases [such as garcinol, curcumin, and histone acetyltransferase (HAT) Inhibitor II]. These results indicate that protein acetylation and deacetylation may represent crucial mechanisms regulating NADPH oxidase-mediated superoxide production. In cell-free systems, incubation of recombinant Rac1 with SIRT1 resulted in decreased Rac1 acetylation. Mass spectrometry analyses identified lysine 166 (K166) in Rac1 as a residue targeted by SIRT1. Deacetylation of Rac1 by SIRT1 markedly reduced the interaction of Rac1 with p67phox in in vitro assays. Computational modeling analyses revealed that K166 deacetylation of Rac1 led to a 5-fold reduction in its binding affinity to guanosine-5'-triphosphate, and a 21-fold decrease in its binding potential to p67phox. The latter is crucial for Rac1-mediated recruitment of p67phox to the membrane and for p67phox activation. In conclusion, both SIRT1 and non-sirtuin deacetylases play a role in regulating NADPH oxidase activity. Rac1 can be directly deacetylated by SIRT1 in a cell-free system, leading to an inhibition of Rac1-p67phox interaction. The downstream targets of non-sirtuin deacetylases are still unknown. The in vivo significance of these findings needs to be investigated in future studies., publishedVersion

Aims: Oxidative stress and inflammation contribute to atherogenesis. Rac1 GTPase regulates pro-oxidant NADPH oxidase activity, reactive oxygen species (ROS) formation, actin cytoskeleton organization and monocyte adhesion. We investigated the vascular effects of pharmacological inhibition of Rac1 GTPase in mice.Methods and Results: We treated wild-type and apolipoprotein E-deficient (ApoE−/−) mice with Clostridium sordellii lethal toxin (LT), a Rac1 inhibitor, and assessed vascular oxidative stress, expression and activity of involved proteins, endothelial function, macrophage infiltration, and atherosclerosis development. LT-treated wild-type mice displayed decreased vascular NADPH oxidase activity and ROS production. Therapeutic LT doses had no impact on behavior, food intake, body weight, heart rate, blood pressure, vascular and myocardial function, differential blood count, and vascular permeability. ApoE−/− mice were fed a cholesterol-rich diet and were treated with LT or vehicle. LT treatment led to decreased aortic Rac1 GTPase activity, NADPH oxidase activity and ROS production, but had no impact on expression and membrane translocation of NADPH oxidase subunits and RhoA GTPase activity. LT-treated mice showed improved aortic endothelium-dependent vasodilation, attenuated atherosclerotic lesion formation and reduced macrophage infiltration of atherosclerotic plaques. Concomitant treatment of cholesterol-fed ApoE−/− mice with LT, the specific synthetic Rac1 inhibitor NSC 23766 or simvastatin comparably reduced aortic Rac1 activity, NADPH oxidase activity, oxidative stress, endothelial dysfunction, atherosclerosis development, and macrophage infiltration.Conclusions: These findings identify an important role of the small GTPase Rac1 in atherogenesis and provide a potential target for anti-atherosclerotic therapy.

Thiol-based redox compounds, namely thioredoxins (Trxs), glutaredoxins (Grxs) and peroxiredoxins (Prxs), stand as a pivotal group of proteins involved in antioxidant processes and redox signaling. Glutaredoxins (Grxs) are considered as one of the major families of proteins involved in redox regulation by removal of S-glutathionylation and thereby reactivation of other enzymes with thiol-dependent activity. Grxs are also coupled to Trxs and Prxs recycling and thereby indirectly contribute to reactive oxygen species (ROS) detoxification. Peroxiredoxins (Prxs) are a ubiquitous family of peroxidases, which play an essential role in the detoxification of hydrogen peroxide, aliphatic and aromatic hydroperoxides, and peroxynitrite. The Trxs, Grxs and Prxs systems, which reversibly induce thiol modifications, regulate redox signaling involved in various biological events in the cardiovascular system. This review focuses on the current knowledge of the role of Trxs, Grxs and Prxs on cardiovascular pathologies and especially in cardiac hypertrophy, ischemia/reperfusion (I/R) injury and heart failure as well as in the presence of cardiovascular risk factors, such as hypertension, hyperlipidemia, hyperglycemia and metabolic syndrome. Further studies on the roles of thiol-dependent redox systems in the cardiovascular system will support the development of novel protective and therapeutic strategies against cardiovascular diseases.

Sepsis causes high mortality in the setting of septic shock. LEADER and other trials revealed cardioprotective and anti-inflammatory properties of glucagon-like peptide-1 (GLP-1) analogs like liraglutide (Lira). We previously demonstrated improved survival in lipopolysaccharide (LPS)-induced endotoxemia by inhibition of GLP-1 degradation. Here we investigate the effects of Lira in the polymicrobial sepsis model of cecal ligation and puncture (CLP). C57BL/6J mice were intraperitoneally injected with Lira (200 µg/kg/d, 3 days) and sepsis induced by CLP after one day of GLP-1 analog treatment. Survival and body temperature were monitored. Aortic vascular function (isometric tension recording), protein expression (immunohistochemistry and dot blot) and gene expression (qRT-PCR) were determined. Endothelium-dependent relaxation in the aorta was impaired by CLP and correlated with markers of inflammation (e.g., interleukin 6 and inducible nitric oxide synthase) and oxidative stress (e.g., 3-nitrotyrosine) was higher in septic mice, all of which was almost completely normalized by Lira therapy. We demonstrate that the GLP-1 analog Lira ameliorates sepsis-induced endothelial dysfunction by the reduction of vascular inflammation and oxidative stress. Accordingly, the findings suggest that the antioxidant and anti-inflammatory effects of GLP-1 analogs may be a valuable tool to protect the cardiovascular system from dysbalanced inflammation in polymicrobial sepsis.

Aims Electronic (e)-cigarettes have been marketed as a ‘healthy’ alternative to traditional combustible cigarettes and as an effective method of smoking cessation. There are, however, a paucity of data to support these claims. In fact, e-cigarettes are implicated in endothelial dysfunction and oxidative stress in the vasculature and the lungs. The mechanisms underlying these side effects remain unclear. Here, we investigated the effects of e-cigarette vapour on vascular function in smokers and experimental animals to determine the underlying mechanisms. Methods and results Acute e-cigarette smoking produced a marked impairment of endothelial function in chronic smokers determined by flow-mediated dilation. In mice, e-cigarette vapour without nicotine had more detrimental effects on endothelial function, markers of oxidative stress, inflammation, and lipid peroxidation than vapour containing nicotine. These effects of e-cigarette vapour were largely absent in mice lacking phagocytic NADPH oxidase (NOX-2) or upon treatment with the endothelin receptor blocker macitentan or the FOXO3 activator bepridil. We also established that the e-cigarette product acrolein, a reactive aldehyde, recapitulated many of the NOX-2-dependent effects of e-cigarette vapour using in vitro blood vessel incubation. Conclusions E-cigarette vapour exposure increases vascular, cerebral, and pulmonary oxidative stress via a NOX-2-dependent mechanism. Our study identifies the toxic aldehyde acrolein as a key mediator of the observed adverse vascular consequences. Thus, e-cigarettes have the potential to induce marked adverse cardiovascular, pulmonary, and cerebrovascular consequences. Since e-cigarette use is increasing, particularly amongst youth, our data suggest that aggressive steps are warranted to limit their health risks.

Noise levels experienced by industrial workers may cause both auditory and non-auditory harmful effects. We have studied the effects of chronic industrial noise exposure on DNA damage, blood pressure, and serum biochemistry in factory workers. Male workers (109 individuals) in three parts of a food factory in Shahroud, Iran were enrolled as the exposed group and male office workers (123 individuals) were the unexposed control group. Noise exposure was measured (dosimetry) and the comet assay was used to evaluate DNA damage in peripheral blood mononuclear cells. Glutathione peroxidase (GPx) and ceruloplasmin (Cp) levels were measured in serum samples. GPx levels, systolic and diastolic blood pressure, and DNA damage were significantly higher in the exposed group than in the control group. However, ceruloplasmin levels were not significantly different. Based on multivariate linear regression analysis, noise exposure was the most important predictor of GPx levels, systolic and diastolic blood pressure, and DNA damage.

Despite extensive efforts to combat cigarette smoking/tobacco use, it still remains a leading cause of global morbidity and mortality, killing more than eight million people each year. While tobacco smoking is a major risk factor for non-communicable diseases related to the four main groups—cardiovascular disease, cancer, chronic lung disease, and diabetes—its impact on neuropsychiatric risk is rather elusive. The aim of this review article is to emphasize the importance of smoking as a potential risk factor for neuropsychiatric disease and to identify central pathophysiological mechanisms that may contribute to this relationship. There is strong evidence from epidemiological and experimental studies indicating that smoking may increase the risk of various neuropsychiatric diseases, such as dementia/cognitive decline, schizophrenia/psychosis, depression, anxiety disorder, and suicidal behavior induced by structural and functional alterations of the central nervous system, mainly centered on inflammatory and oxidative stress pathways. From a public health perspective, preventive measures and policies designed to counteract the global epidemic of smoking should necessarily include warnings and actions that address the risk of neuropsychiatric disease.

Vascular oxidative stress, inflammation, and subsequent endothelial dysfunction are consequences of traditional cardiovascular risk factors, all of which contribute to cardiovascular disease. Environmental stressors, such as traffic noise and air pollution, may also facilitate the development and progression of cardiovascular and metabolic diseases. In our previous studies, we investigated the influence of aircraft noise exposure on molecular mechanisms, identifying oxidative stress and inflammation as central players in mediating vascular function. The present study investigates the role of heme oxygenase-1 (HO-1) as an antioxidant response preventing vascular consequences following exposure to aircraft noise. C57BL/6J mice were treated with the HO-1 inducer hemin (25 mg/kg i.p.) or the NRF2 activator dimethyl fumarate (DMF, 20 mg/kg p.o.). During therapy, the animals were exposed to noise at a maximum sound pressure level of 85 dB(A) and a mean sound pressure level of 72 dB(A). Our data showed a marked protective effect of both treatments on animals exposed to noise for 4 days by normalization of arterial hypertension and vascular dysfunction in the noise-exposed groups. We observed a partial normalization of noise-triggered oxidative stress and inflammation by hemin and DMF therapy, which was associated with HO-1 induction. The present study identifies possible new targets for the mitigation of the adverse health effects caused by environmental noise exposure. Since natural dietary constituents can achieve HO-1 and NRF2 induction, these pathways represent promising targets for preventive measures.

Synaptic signaling depends on ATP generated by mitochondria. Due to extensive connectivity, the striatum is especially vulnerable to mitochondrial dysfunction and thus requires efficient mitochondrial quality control. We found that the neuronal calcium-binding protein NECAB2 ensures synaptic function in the striatum by increasing mitochondrial efficiency. NECAB2 associates with early endosomes and mitochondria at striatal synapses. Loss of NECAB2 dysregulates proteins of the endosomal ESCRT machinery and oxidative phosphorylation. Mitochondria from NECAB2-deficient mice are more abundant but less efficient. These mitochondria exhibit increased respiration and superoxide production but produce less ATP. This accumulation of faulty mitochondria is caused by a defective assembly of mitochondria with early endosomes in response to oxidative stress. Impairment of this mechanism causes loss of striatal synapses and behavioral dysfunctions such as reduced motivation and altered sensory gating. NECAB2 therefore orchestrates an endosomal pathway of mitochondrial quality control important for striatal function.

The power of the sun can be harvested with a solar cell, and much effort has been put into making this process more efficient. This thesis is about a novel type of solar cell that has a higher theoretical efficiency, the Singlet Fission-silicon solar cell. This new type of solar cell can use the energy in the different colors of the light more efficiently. The Singlet Fission layer absorbs light with a high energy and splits the energy into smaller energy packets, that are then transferred into a silicon solar cell. The silicon solar cell absorbs all low energy light and together, both layers use more of the energy in the solar spectrum for energy generation. So far, the transfer of energy is the main bottleneck in this process. In this thesis we first describe a way to use quantum dots as a layer that facilitates the energy transfer in between the Singlet Fission layer and silicon. Then, we describe a new optical method to detect the transfer of energy. We also manufacture a real-world Singlet Fission-Silicon solar cell and use the special behavior of the Singlet Fission process under a magnetic field to detect the energy transfer, and show that the change in the crystal structure in the Singlet Fission material is responsible for the transfer of energy. With these new techniques and insights, we hope that real life Singlet Fission-silicon solar cells have become closer to realization.

Arterial hypertension is one of the major health risk factors leading to coronary artery disease, stroke or peripheral artery disease. Dietary uptake of inorganic nitrite (NO2−) and nitrate (NO3−) via vegetables leads to enhanced vascular NO bioavailability and provides antihypertensive effects. The present study aims to understand the underlying vasoprotective effects of nutritional NO2− and NO3− co-therapy in mice with angiotensin-II (AT-II)-induced arterial hypertension. High-dose AT-II (1 mg/kg/d, 1w, s. c.) was used to induce arterial hypertension in male C57BL/6 mice. Additional inorganic nitrite (7.5 mg/kg/d, p. o.) or nitrate (150 mg/kg/d, p. o.) were administered via the drinking water. Blood pressure (tail-cuff method) and endothelial function (isometric tension) were determined. Oxidative stress and inflammation markers were quantified in aorta, heart, kidney and blood. Co-treatment with inorganic nitrite, but not with nitrate, normalized vascular function, oxidative stress markers and inflammatory pathways in AT-II treated mice. Of note, the highly beneficial effects of nitrite on all parameters and the less pronounced protection by nitrate, as seen by improvement of some parameters, were observed despite no significant increase in plasma nitrite levels by both therapies. Methemoglobin levels tended to be higher upon nitrite/nitrate treatment. Nutritional nitric oxide precursors represent a non-pharmacological treatment option for hypertension that could be applied to the general population (e.g. by eating certain vegetables). The more beneficial effects of inorganic nitrite may rely on superior NO bioactivation and stronger blood pressure lowering effects. Future large-scale clinical studies should investigate whether hypertension and cardiovascular outcome in general can be influenced by dietary inorganic nitrite therapy.

Aircraft noise induces vascular and cerebral inflammation and oxidative stress causing hypertension and cardiovascular/cerebral dysfunction. With the present studies, we sought to determine the role of myeloid cells in the vascular vs. cerebral consequences of exposure to aircraft noise. Toxin-mediated ablation of lysozyme M+ (LysM+) myeloid cells was performed in LysMCreiDTR mice carrying a cre-inducible diphtheria toxin receptor. In the last 4d of toxin treatment, the animals were exposed to noise at maximum and mean sound pressure levels of 85 and 72 dB(A), respectively. Flow cytometry analysis revealed accumulation of CD45+, CD11b+, F4/80+, and Ly6G−Ly6C+ cells in the aortas of noise-exposed mice, which was prevented by LysM+ cell ablation in the periphery, whereas brain infiltrates were even exacerbated upon ablation. Aircraft noise-induced increases in blood pressure and endothelial dysfunction of the aorta and retinal/mesenteric arterioles were almost completely normalized by ablation. Correspondingly, reactive oxygen species in the aorta, heart, and retinal/mesenteric vessels were attenuated in ablated noise-exposed mice, while microglial activation and abundance in the brain was greatly increased. Expression of phagocytic NADPH oxidase (NOX-2) and vascular cell adhesion molecule-1 (VCAM-1) mRNA in the aorta was reduced, while NFκB signaling appeared to be activated in the brain upon ablation. In sum, we show dissociation of cerebral and peripheral inflammatory reactions in response to aircraft noise after LysM+ cell ablation, wherein peripheral myeloid inflammatory cells represent a dominant part of the pathomechanism for noise stress-induced cardiovascular effects and their central nervous counterparts, microglia, as key mediators in stress responses.

Global epidemiological studies show that chronic non-communicable diseases such as atherosclerosis and metabolic disorders represent the leading cause of premature mortality and morbidity. Cardiovascular disease such as ischemic heart disease is a major contributor to the global burden of disease and the socioeconomic health costs. Clinical and epidemiological data show an association of typical oxidative stress markers such as lipid peroxidation products, 3-nitrotyrosine or oxidized DNA/RNA bases with all major cardiovascular diseases. This supports the concept that the formation of reactive oxygen and nitrogen species by various sources (NADPH oxidases, xanthine oxidase and mitochondrial respiratory chain) represents a hallmark of the leading cardiovascular comorbidities such as hyperlipidemia, hypertension and diabetes. These reactive oxygen and nitrogen species can lead to oxidative damage but also adverse redox signaling at the level of kinases, calcium handling, inflammation, epigenetic control, circadian clock and proteasomal system. The in vivo footprints of these adverse processes (redox biomarkers) are discussed in the present review with focus on their clinical relevance, whereas the details of their mechanisms of formation and technical aspects of their detection are only briefly mentioned. The major categories of redox biomarkers are summarized and explained on the basis of suitable examples. Also the potential prognostic value of redox biomarkers is critically discussed to understand what kind of information they can provide but also what they cannot achieve., Graphical abstract Image 1, Highlights • Global burden of disease, oxidative stress and cardiovascular disease (CVD). • Discussion of the different categories of redox biomarkers in CVD. • Discussion of prognostic value of classical oxidative stress markers in human CVD. • Discussion of novel redox biomarkers for risk stratification in human CVD. • Highlighting the additivity of redox biomarkers in human CVD comorbidities.

Global epidemiological studies reported a shift from maternal/infectious communicable diseases to chronic non-communicable diseases and a major part is attributable to atherosclerosis and metabolic disorders. Accordingly, ischemic heart disease was identified as a leading risk factor for global mortality and morbidity with a prevalence of 128 million people. Almost 9 million premature deaths can be attributed to ischemic heart disease and subsequent acute myocardial infarction and heart failure, also representing a substantial socioeconomic burden. As evidenced by typical oxidative stress markers such as lipid peroxidation products or oxidized DNA/RNA bases, the formation of reactive oxygen species by various sources (NADPH oxidases, xanthine oxidase and mitochondrial resperatory chain) plays a central role for the severity of ischemia/reperfusion damage. The underlying mechanisms comprise direct oxidative damage but also adverse redox-regulation of kinase and calcium signaling, inflammation and cardiac remodeling among others. These processes and the role of reactive oxygen species are discussed in the present review. We also present and discuss potential targets for redox-based therapies that are either already established in the clinics (e.g. guanylyl cyclase activators and stimulators) or at least successfully tested in preclinical models of myocardial infarction and heart failure (mitochondria-targeted antioxidants). However, reactive oxygen species have not only detrimental effects but are also involved in essential cellular signaling and may even act protective as seen by ischemic pre- and post-conditioning or eustress - which makes redox therapy quite challenging.

Background In the setting of myocardial infarction (MI), patients with coronary no-reflow and/or delayed presentation after onset of symptoms (sub-acute MI) are inflicted by severe thrombo-inflammation and are marked by worse clinical outcome. However, it is unclear whether tissue factor (TF) contributes to outcome post MI solely by the regulatory functions of its cytoplasmic tail independently of its coagulation activity. Purpose We analyzed the role of the TF cytoplasmic domain in the recruitment of myeloid cells into the infarcted myocardium and the consequences on cardiac remodeling, scar formation, development of heart failure and survival post MI. Methods Twelve Patients enrolled in the MICAT (Mainzer Intracoronary Database, ClinicalTrials.gov Identifier: NCT02180178) study were examined. Patients with sub-acute MI and stable coronary artery disease were defined and monocytes were isolated from peripheral blood mononuclear cells (PBMCs). Human heart samples acquired from the left ventricular wall of explanted hearts following cardiac transplantation or obtained during implantation of left ventricular assist device. Samples were investigated for downstream analysis of protein by western blots, RNA quantification and cryo-sectioning. MI was induced in 9 to 12 weeks old male C57BL/6J mice, mice specifically lacking the cytoplasmic tail (CT) of TF (TFΔCT mice) and TFfl/flLysMCre+/− mice by permanent ligation of the left anterior descending artery. Left ventricular function was assessed by High-Frequency Ultrasound System. Infiltration of immune cells into the infarcted myocardium was analyzed by performing flow cytometric analysis after enzymatic digestion of the myocardium. Superoxide levels were quantified by HPLC-based measurement of dihydroethidium derived oxidation product 2-hydroxy ethidium. Results Circulating monocytes in patients with sub-acute MI showed increased nitrosative stress as well as increased phosphorylation of TF CT along with TGF-β1 and NF-kB inflammatory activation, which was recapitulated in cardiac tissue of end-stage heart failure patients with chronic MI. MI results in phosphorylation of the CT of TF within myeloid cells. Using mice with conditional knockout of TF on myeloid cells or TFΔCT mice, we found that this regulatory intracellular domain of TF within myeloid cells is required for cardiac infiltration of inflammatory Ly6Chigh TF+ monocytes, Rac-1 GTPase and superoxide formation of gp91phox + myeloid cells in MI. TGF-β1 dependent SMAD2 activation and cardiac collagen deposition as late sequel of MI was reduced in TFΔCT mice, resulting in attenuated cardiac dysfunction and reduced mortality. Conclusion We conclude that, TF CT drives NADPH-oxidase derived superoxide formation, thrombo-inflammation and cardiac fibrosis. Therefore, it might serve as putative biomarker and risk predictor in MI Funding Acknowledgement Type of funding source: None

Cardiac and vascular diseases are often associated with increased oxidative stress and inflammation, and both may contribute to the disease progression. However, successful applications of antioxidants in the clinical setting are very rare and specific anti-inflammatory therapeutics only emerged recently. Reasons for this rely on the great diversity of oxidative stress and inflammatory cells that can either act as cardioprotective or cause tissue damage in the heart. Recent large-scale clinical trials found that highly specific anti-inflammatory therapies using monoclonal antibodies against cytokines resulted in lower cardiovascular mortality in patients with pre-existing atherosclerotic disease. In addition, unspecific antiinflammatory medication and established cardiovascular drugs with pleiotropic immunomodulatory properties such as angiotensin converting enzyme (ACE) inhibitors or statins have proven beneficial cardiovascular effects. Normalization of oxidative stress seems to be a common feature of these therapies, which can be explained by a close interaction/crosstalk of the cellular redox state and inflammatory processes. In this review, we give an overview of cardiac reactive oxygen species (ROS) sources and processes of cardiac inflammation as well as the connection of ROS and inflammation in ischemic cardiomyopathy in order to shed light on possible cardioprotective interventions.

Efficient light management is essential to achieve high-efficiency solar cell geometries: ensuring the absorption of sunlight in the active region is a fundamental principle of a photovoltaic device. By controlling the spectrum and angular distribution of light in the device, the absorption in the active region can be enhanced. We investigate two solar cell geometries in which we control the directional emission of quantum dots (QDs): a tetracene\Si solar cell based on singlet-triplet down-conversion and a luminescent solar concentrator (LSC) device.

In this work, we investigate a tetracene/Si singlet-triplet down-conversion solar cell geometry in which we control the directional emission of quantum dots (QDs). In this system, photons in the visible range (450-550 nm) excite high-energy singlet-excitons in tetracene that rapidly convert into two triplet-excitons at about half the energy. The triplet-exciton energy is transferred to the QDs that subsequently emit at 1000-1100 nm. A significant loss channel is the QD emission that is directed upwards, so anisotropic downward emission into the underlying Si cell is essential. Here, we demonstrate directional light emission of CdSe/ZnS core-shell quantum dots (QDs) coupled to Si Mie resonators fabricated on a Si solar cell. By varying the shape and size of the Mie resonator, interference of the electric and magnetic multipolar modes supported by the resonator is controlled. Placing the QDs in the near-field of the resonator enables efficient coupling of the QD transition dipole with these multipolar modes. Using numerical FDTD calculations we show that the QD emission is efficiently directed into the solar cell. We fabricate nanostructures on a Si substrate using electron-beam lithography and reactive-ion etching. Using soft-stamp imprinting we selectively print CdSe/ZnS QDs (peak emission 800 nm) on top of the nanostructures. We then map the QD emission anisotropy for different Mie resonator sizes, using photoluminescence spectroscopy. Photoluminescence lifetimes show a systematic increase from 7 ns to 17 ns, for Si nanocylinder diameter from 200 to 425 nm (cylinder height 125 nm), consistent with the varying nanostructure resonances as found in FDTD simulations. The anisotropic downward emission demonstrated in this work of QDs coupled to Si nanostructures can enhance the efficiency of a tetracene/Si down-conversion system. Moreover, this work can impact a broad range of other applications in which directional emission is relevant, in solid-state lighting, integrated optics, and photovoltaics.

Environmental pollution and non-chemical stressors such as mental stress or traffic noise exposure are increasingly accepted as health risk factors with substantial contribution to chronic noncommunicable diseases (e.g. cardiovascular, metabolic and mental). Whereas the mechanisms of air pollution-mediated adverse health effects are well characterized, the mechanisms of traffic noise exposure are not completely understood, despite convincing clinical and epidemiological evidence for a significant contribution of environmental noise to overall mortality and disability. The initial mechanism of noise-induced cardiovascular, metabolic and mental disease is well defined by the „noise reaction model“ and consists of neuronal activation involving the hypothalamic-pituitary-adrenal (HPA) axis as well as the sympathetic nervous system, followed by a classical stress response via cortisol and catecholamines. Stress pathways are initiated by noise-induced annoyance and sleep deprivation/fragmentation. This review highlights the down-stream pathophysiology of noise-induced mental stress, which is based on an induction of inflammation and oxidative stress. We highlight the sources of reactive oxygen species (ROS) involved and the known targets for noise-induced oxidative damage. Part of the review emphasizes noise-triggered uncoupling/dysregulation of endothelial and neuronal nitric oxide synthase (eNOS and nNOS) and its central role for vascular dysfunction., Graphical abstract Image 1, Highlights • Exposure to (traffic) noise causes non-auditory (indirect) cardiovascular and cerebral health harms via neuronal activation. • Noise activates the HPA axis and sympathetic nervous system increasing levels of stress hormones, vasoconstrictors and ROS. • Noise induces inflammation and stimulates several ROS sources leading to cerebral and cardiovascular oxidative damage. • Noise leads to eNOS and nNOS uncoupling contributing to cardiometabolic disease and cognitive impairment.

Redox signalling in mitochondria plays an important role in myocardial ischaemia/reperfusion (I/R) injury and in cardioprotection. Reactive oxygen and nitrogen species (ROS/RNS) modify cellular structures and functions by means of covalent changes in proteins including among others S‐nitros(yl)ation by nitric oxide (NO) and its derivatives, and S‐sulphydration by hydrogen sulphide (H2S). Many enzymes are involved in the mitochondrial formation and handling of ROS, NO and H2S under physiological and pathological conditions. In particular, the balance between formation and removal of reactive species is impaired during I/R favouring their accumulation. Therefore, various interventions aimed at decreasing mitochondrial ROS accumulation have been developed and have shown cardioprotective effects in experimental settings. However, ROS, NO and H2S play also a role in endogenous cardioprotection, as in the case of ischaemic pre‐conditioning, so that preventing their increase might hamper self‐defence mechanisms. The aim of the present review was to provide a critical analysis of formation and role of reactive species, NO and H2S in mitochondria, with a special emphasis on mechanisms of injury and protection that determine the fate of hearts subjected to I/R. The elucidation of the signalling pathways of ROS, NO and H2S is likely to reveal novel molecular targets for cardioprotection that could be modulated by pharmacological agents to prevent I/R injury.

The rational combination of tetracene Tc with crystalline silicon c Si could greatly enhance c Si solar cell efficiencies via singlet fission. The Tc c Si energy level alignment ELA is thought to be central to controlling the required interface transfer processes. We modified hydrogen terminated c Si H Si with 2,2 amp; 8242; perfluoronaphthalene 2,6 diylidene dimalononitrile F6TCNNQ , C60, or NF3 and probed the effect on the c Si surface chemistry, the Tc c Si ELA, the Tc morphology, and solar cell characteristics using ultraviolet and X ray photoelectron spectroscopy, atomic force microscopy, X ray diffraction, photoluminescence transients, device measurements, and transfer matrix optical modeling. Submonolayer interlayers of F6TCNNQ shifted the Tc H Si 111 ELA by up to 0.55 eV. C60 showed no notable effect on the ELA and proved detrimental for the Tc film morphology and solar cell performance. Neither F6TCNNQ nor C60 improved the Tc related photocurrent significantly. NF3 CVD substituted the H termination of H Si 100 with more electronegative species and resulted in work functions as high as 6 eV. This changed the Tc H Si 100 ELA by up to 0.45 eV. NF3 plasma from a remote source caused pronounced c Si oxidation and a diminished c Si photoluminescence lifetime, which was not observed for NF3 plasma created in close proximity to the c Si surface or neutral NF3. We discuss possible reasons for why the improved ELA does not lead to an improved singlet fission harvest

Oxidative stress plays a key role for the development of cardiovascular, metabolic, and neurodegenerative disease. This concept has been proven by using the approach of genetic deletion of reactive oxygen and nitrogen species (RONS) producing, pro-oxidant enzymes as well as by the overexpression of RONS detoxifying, antioxidant enzymes leading to an amelioration of the severity of diseases. Vice versa, the development and progression of cardiovascular diseases is aggravated by overexpression of RONS producing enzymes as well as deletion of RONS detoxifying enzymes. We have previously identified cross talk mechanisms between different sources of RONS, which can amplify the oxidative stress-mediated damage. Here, the pathways and potential mechanisms leading to this cross talk are analyzed in detail and highlighted by selected examples from the current literature and own data including hypoxia, angiotensin II (AT-II)-induced hypertension, nitrate tolerance, aging, and others. The general concept of redox-based activation of RONS sources via “kindling radicals” and enzyme-specific “redox switches” as well as the interaction with redox-sensitive inflammatory pathways are discussed. Here, we present evidence for the existence of such cross talk mechanisms in the setting of diabetes and critically assess their contribution to the severity of diabetic complications.

Reactive oxygen and nitrogen species (RONS) cause oxidative damage, which is associated with endothelial dysfunction and cardiovascular disease, but may also contribute to redox signaling. Therefore, their precise detection is important for the evaluation of disease mechanisms. Here, we compared three different methods for the detection of 3-nitrotyrosine (3-NT), a marker of nitro-oxidative stress, in biological samples. Nitrated proteins were generated by incubation with peroxynitrite or 3-morpholino sydnonimine (Sin-1) and subjected to total hydrolysis using pronase, a mixture of different proteases. The 3-NT was then separated by high performance liquid chromatography (HPLC) and quantified by electrochemical detection (ECD, CoulArray) and compared to classical methods, namely enzyme-linked immunosorbent assay (ELISA) and dot blot analysis using specific 3-NT antibodies. Calibration curves for authentic 3-NT (detection limit 10 nM) and a concentration-response pattern for 3-NT obtained from digested nitrated bovine serum albumin (BSA) were highly linear over a wide 3-NT concentration range. Also, ex vivo nitration of protein from heart, isolated mitochondria, and serum/plasma could be quantified using the HPLC/ECD method and was confirmed by LC-MS/MS. Of note, nitro-oxidative damage of mitochondria results in increased superoxide (O2&bull, &ndash, ) formation rates (measured by dihydroethidium-based HPLC assay), pointing to a self-amplification mechanism of oxidative stress. Based on our ex vivo data, the CoulArray quantification method for 3-NT seems to have some advantages regarding sensitivity and selectivity. Establishing a reliable automated HPLC assay for the routine quantification of 3-NT in biological samples of cell culture, of animal and human origin seems to be more sophisticated than expected.

Singlet fission in tetracene generates two triplet excitons per absorbed photon. If these triplet excitons can be effectively transferred into silicon (Si) then additional photocurrent can be generated from photons above the bandgap of Si. This could alleviate the thermalization loss and increase the efficiency of conventional Si solar cells. Here we show that a change in the polymorphism of tetracene deposited on Si due to air exposure, facilitates triplet transfer from tetracene into Si. Magnetic field-dependent photocurrent measurements confirm that triplet excitons contribute to the photocurrent. The decay of tetracene delayed photoluminescence was used to determine a triplet transfer time of 215 ns and a maximum yield of triplet transfer into Si of ~50 %. Our study suggests that control over the morphology of tetracene during deposition will be of great importance to boost the triplet transfer yield further.

CONTEXT: We hypothesized that TSH-receptor (TSHR) stimulating antibodies (TSAbs) are involved in oxidative stress mechanisms in patients with Graves disease (GD). METHODS: Nicotinamide adenine dinucleotide phosphate oxidase, isoform 2 (NOX2); oxidative parameters; and oxidative burst were measured in serum, urine, and whole blood from patients with GD and control subjects. Superoxide production was investigated in human embryonic kidney (HEK)-293 cells stably overexpressing the TSHR. Lipid peroxidation was determined by immunodot-blot analysis for protein-bound 4-hydroxy-2-nonenal (4-HNE) in human primary thyrocytes and HEK-293–TSHR cells. RESULTS: Serum NOX2 levels were markedly higher in hyperthyroid untreated vs euthyroid treated patients with GD, hyperthyroid patients with toxic nodular goiter, and euthyroid healthy control subjects (all P < 0.0001). Urine oxidative parameters were increased in patients with GD vs patients with toxic goiter (P < 0.01) and/or control subjects (P < 0.001). The maximum of the zymosan A- and phorbol 12,13-dibutyrate–induced respiratory burst of leukocytes was 1.5-fold higher in whole blood from hyperthyroid patients with GD compared with control subjects (P < 0.001 and P < 0.05). Monoclonal M22 TSAbs stimulated cAMP (HEK cells) in a dose-dependent manner. M22 (P = 0.0082), bovine TSH (P = 0.0028), and sera of hyperthyroid patients with GD (P < 0.05) increased superoxide-specific 2-hydroxyethidium levels in HEK-293 TSHR cells after 48-hour incubation vs control subjects. In contrast, triiodothyronine (T3) did not affect reactive oxygen species (ROS) production. In primary thyrocytes, the 4-HNE marker was higher in patients with GD vs control subjects at 6 and 48 hours (P = 0.02 and P = 0.04, respectively). Further, after 48-hour incubation of HEK-293 TSHR cells with patient sera, 4-HNE was higher in patients with untreated GD compared with control subjects (P < 0.05). CONCLUSIONS: Monoclonal M22 and polyclonal serum TSAbs augment ROS generation and/or induce lipid peroxidation.

Aims Immune cell function involves energy-dependent processes including growth, proliferation, and cytokine production. Since the AMP-activated protein kinase (AMPK) is a crucial regulator of intracellular energy homeostasis, its expression and activity may also affect innate and adaptive immune cell responses. Therefore, we aimed to investigate the consequences of α1AMPK deletion in myelomonocytic cells on vascular function, inflammation, and hypertension during chronic angiotensin II (ATII) treatment. Methods and results We generated a mouse strain with α1AMPK deletion in lysozyme M+ myelomonocytic cells. Compared to controls, chronic ATII infusion (1 mg/kg/day for 7 days) lead to increased vascular oxidative stress and aggravated endothelial dysfunction in LysM-Cre+ x α1AMPKfl/fl mice. This was accompanied by an increased aortic infiltration of CD11b+F4/80+ macrophages and enhanced pro-inflammatory cytokine release (tumour necrosis factor-alpha, interferon-gamma, and interleukin-6). Mechanistically, we found that increased expression of C-C chemokine receptor 2 (CCR2) in α1AMPK deficient myelomonocytic cells facilitated their recruitment to the vascular wall. In addition, expression of the ATII receptor type 1a and the oxidative burst was increased in these cells, indicating an increased susceptibility towards pro-oxidant stimuli. Conclusions In summary, α1AMPK deletion in myelomonocytic cells aggravates vascular oxidative stress and dysfunction by enhancing their recruitment to the vascular wall and increasing their susceptibility towards pro-oxidant stimuli. Our observations suggest that metabolic control in myelomonocytic cells has profound implications for their inflammatory phenotype and may trigger the development of vascular disease.

In 1867 the organic nitrite, amyl nitrite, was introduced as a therapeutic agent in the treatment of angina pectoris and was later substituted by the organic nitrate nitroglycerin (NTG). Despite having a highly potent vasodilator capacity in veins>coronary arteries>arterioles, the vasodilator effects NTG are rapidly attenuated by the development of nitrate tolerance. We and others established that NTG treatment stimulates the production of reactive oxygen species such as superoxide and peroxynitrite with subsequent marked attenuation of the NTG vasodilator potency. The nitrite anion (NO2-) has more recently been characterized to possess novel pharmacotherapeutic actions such as modulation of vasodilation under hypoxic conditions, thereby providing protection in ischemia-reperfusion injury. Administration of NO2-/NO3- has also been shown to improve myocardial function in heart failure and to lower blood pressure. Despite these positive aspects there is still a great need to study inorganic nitrate and nitrite therapy in various cardiovascular diseases in prospective outcome directed studies. In case being successful, this kind of therapy would indeed represent a cheap, therefore affordable, effective cardiovascular therapy without major side effects as observed in response to therapy with organic nitrates.

B lymphocytes have been implicated in the development of insulin resistance, atherosclerosis and certain types of hypertension. In contrast to these studies, which were performed under pathological conditions, the present study provides evidence for the protective effect of B lymphocytes in maintaining vascular homeostasis under physiological conditions. In young mice not exposed to any known risk factors, the lack of B cells led to massive endothelial dysfunction. The vascular dysfunction in B cell-deficient mice was associated with an increased number of neutrophils in the circulating blood. Neutrophil depletion in B cell-deficient mice resulted in the complete normalization of vascular function, indicating a causal role of neutrophilia. Moreover, vascular function in B cell-deficient mice could be restored by adoptive transfer of naive B-1 cells isolated from wild-type mice. Interestingly, B-1 cell transfer also reduced the number of neutrophils in the recipient mice, further supporting the involvement of neutrophils in the vascular pathology caused by B cell-deficiency. In conclusion, we report in the present study the hitherto undescribed role of B lymphocytes in regulating vascular function. B cell dysregulation may represent a crucial mechanism in vascular pathology.

Aims Doxorubicin (DOX) is an important drug for the treatment of various tumor entities. However, the occurrence of heart failure limits its application. This study investigated differential gene expression profiles in the left and right ventricles of DOX treated mice with either preserved or impaired myocardial function. We provide new mechanistic insights into the pathophysiology of DOX-induced heart failure and have discovered pathways that counteract DOX-induced cardiotoxicity. Main methods We used in total 48 male mice and applied a chronic low dose DOX administration (5 mg/kg per injection, in total 20 mg/kg over 4 weeks) to induce heart failure. Echocardiographic parameters were evaluated one week after the final dose and mice were separated according to functional parameters into doxorubicin responding and non-responding animals. Post mortem, measurements of reactive oxygen species (ROS) and gene expression profiling was performed in separated right and left hearts. Key findings We detected significant ROS production in the left heart of the mice in response to DOX treatment, although interestingly, not in the right heart. We found that transcriptional changes differ between right and left heart correlating with the occurrence of myocardial dysfunction. Significance Doxorubicin induces changes in gene expression in the entire heart of animals without necessarily impairing cardiac function. We identified a set of transcripts that are associated with DOX cardiotoxicity. These might represent promising targets to ameliorate DOX-induced heart failure. Moreover, our results emphasize that parameters of left and right heart function should be evaluated during standardized echocardiography in patients undergoing DOX therapy.

Background/Aims: 2-aminoethyl nitrate (CLC-1011) is a member of the class of organic nitrates that cause vasodilation by the generation of nitric oxide (•NO). These drugs are mainly used for the treatment of angina pectoris and ischemic heart disease. The aim of this study was to characterize the vasodilatory potency of this organic nitrate alone and in combination with clinically established cardiovascular drugs. Methods: Vasodilation by CLC-1011 was tested by isometric tension studies, either alone or combined with cilostazol, valsartan, and metoprolol. Induction of oxidative stress in isolated heart mitochondria was measured by enhanced chemiluminescence. Bioactivation of CLC-1011 in aortic tissue was measured by electron paramagnetic resonance spectroscopy using an iron-based spin trap for •NO. Results: We observed potent vasodilation by CLC-1011 and additive effects for all three drug combinations. In contrast to nitroglycerin (GTN), CLC-1011 did not stimulate mitochondrial oxidative stress. CLC-1011 was bioactivated to •NO in aortic tissue. Conclusion: In summary, the experiments described in this report demonstrate that CLC-1011 does not induce oxidative stress, is a more potent vasodilator than isosorbide-5-mononitrate and dinitrate ISDN, and displays synergistic vasodilation with other cardiovascular drugs. CLC-1011 fixed dose combinations could be used in the management of cardiovascular diseases.

Aims CD40 ligand (CD40L) signaling controls vascular oxidative stress and related dysfunction in angiotensin-II-induced arterial hypertension by regulating vascular immune cell recruitment and platelet activation. Here we investigated the role of CD40L in experimental hyperlipidemia. Methods and results Male wild type and CD40L−/− mice (C57BL/6 background) were subjected to high fat diet for sixteen weeks. Weight, cholesterol, HDL, and LDL levels, endothelial function (isometric tension recording), oxidative stress (NADPH oxidase expression, dihydroethidium fluorescence) and inflammatory parameters (inducible nitric oxide synthase, interleukin-6 expression) were assessed. CD40L expression, weight, leptin and lipids were increased, and endothelial dysfunction, oxidative stress and inflammation were more pronounced in wild type mice on a high fat diet, all of which was almost normalized by CD40L deficiency. Similar results were obtained in diabetic db/db mice with CD40/TRAF6 inhibitor (6877002) therapy. In a small human study higher serum sCD40L levels and an inflammatory phenotype were detected in the blood and Aorta ascendens of obese patients (body mass index > 35) that underwent by-pass surgery. Conclusion CD40L controls obesity-associated vascular inflammation, oxidative stress and endothelial dysfunction in mice and potentially humans. Thus, CD40L represents a therapeutic target in lipid metabolic disorders which is a leading cause in cardiovascular disease.

Reactive oxygen and nitrogen species (ROS and RNS, e.g. H2O2, nitric oxide) confer redox regulation of essential cellular signaling pathways such as cell differentiation, proliferation, migration and apoptosis. At higher concentrations, ROS and RNS lead to oxidative stress and oxidative damage of biomolecules (e.g. via formation of peroxynitrite, fenton chemistry). Peripheral artery disease (PAD) is characterized by severe ischemic conditions in the periphery leading to intermittent claudication and critical limb ischemia (end stage). It is well known that redox biology and oxidative stress play an important role in this setting. We here discuss the major pathways of oxidative stress and redox signaling underlying the disease progression with special emphasis on the contribution of inflammatory processes. We also highlight therapeutic strategies comprising pharmacological (e.g. statins, angiotensin-converting enzyme inhibitors, phosphodiesterase inhibition) and non-pharmacological (e.g. exercise) interventions. Both of these strategies induce potent indirect antioxidant and anti-inflammatory mechanisms that may contribute to an improvement of PAD associated complications and disease progression by removing excess formation of ROS and RNS (e.g. by ameliorating primary complications such as hyperlipidemia and hypertension) as well as the normalization of the inflammatory phenotype suppressing the progression of atherosclerosis. Keywords: Oxidative stress, Redox signaling, Peripheral artery (occlusive) disease, Claudication and critical limb ischemia, Walking distance, Antioxidant therapy

Oxidative stress is a major hallmark of cardiovascular diseases although a causal link was so far not proven by large clinical trials. However, there is a close association between oxidative stress and inflammation and increasing evidence for a causal role of (low-grade) inflammation for the onset and progression of cardiovascular diseases, which may serve as the missing link between oxidative stress and cardiovascular morbidity and mortality. With the present review we would like to highlight the multiple redox regulated pathways in inflammation, discuss the sources of reactive oxygen and nitrogen species that are of interest for these processes and finally discuss the importance of angiotensin II (AT-II) as a trigger of cardiovascular inflammation and the initiation and progression of cardiovascular diseases.

Background: Reactive oxygen and nitrogen species (RONS such as H2O2, nitric oxide) are generated within the organism. Whereas physiological formation rates confer redox regulation of essential cellular functions and provide the basis for adaptive stress responses, their excessive formation contributes to impaired cellular function or even cell death, organ dysfunction and severe disease phenotypes of the entire organism. Therefore, quantification of RONS formation and knowledge of their tissue/cell/compartment-specific distribution is of great biological and clinical importance. Methods: Here, we used a high-performance/pressure liquid chromatography (HPLC) assay to quantify the superoxide-specific oxidation product of the mitochondria-targeted fluorescence dye triphenylphosphonium-linked hydroethidium (mitoSOX) in biochemical systems and three animal models with established oxidative stress. Type 1 diabetes (single injection of streptozotocin), hypertension (infusion of angiotensin-II for 7 days) and nitrate tolerance (infusion of nitroglycerin for 4 days) was induced in male Wistar rats. Results: The usefulness of mitoSOX/HPLC for quantification of mitochondrial superoxide was confirmed by xanthine oxidase activity as well as isolated stimulated rat heart mitochondria in the presence or absence of superoxide scavengers. Vascular function was assessed by isometric tension methodology and was impaired in the rat models of oxidative stress. Vascular dysfunction correlated with increased mitoSOX oxidation but also classical RONS detection assays as well as typical markers of oxidative stress. Conclusion: mitoSOX/HPLC represents a valid method for detection of mitochondrial superoxide formation in tissues of different animal disease models and correlates well with functional parameters and other markers of oxidative stress.

Objective. Glaucoma is a leading cause of severe visual impairment and blindness. Although high intraocular pressure (IOP) is an established risk factor for the disease, the role of abnormal ocular vessel function in the pathophysiology of glaucoma gains more and more attention. We tested the hypothesis that elevated intraocular pressure (IOP) causes vascular dysfunction in the retina. Methods. High IOP was induced in one group of mice by unilateral cauterization of three episcleral veins. The other group received sham surgery only. Two weeks later, retinal vascular preparations were studied by video microscopy in vitro. Reactive oxygen species (ROS) levels and expression of hypoxia markers and of prooxidant and antioxidant redox genes as well as of inflammatory cytokines were determined. Results. Strikingly, responses of retinal arterioles to stepwise elevation of perfusion pressure were impaired in the high-IOP group. Moreover, vasodilation responses to the endothelium-dependent vasodilator, acetylcholine, were markedly reduced in mice with elevated IOP, while no differences were seen in response to the endothelium-independent nitric oxide donor, sodium nitroprusside. Remarkably, ROS levels were increased in the retinal ganglion cell layer including blood vessels. Expression of the NADPH oxidase isoform, NOX2, and of the inflammatory cytokine, TNF-α, was increased at the mRNA level in retinal explants. Expression of NOX2, but not of the hypoxic markers, HIF-1α and VEGF-A, was increased in the retinal ganglion cell layer and in retinal blood vessels at the protein level. Conclusion. Our data provide first-time evidence that IOP elevation impairs autoregulation and induces endothelial dysfunction in mouse retinal arterioles. Oxidative stress and inflammation, but not hypoxia, appear to be involved in this process.

The anthracycline doxorubicin (DOX) is widely used in cancer therapy with the limitation of cardiotoxicity leading to the development of congestive heart failure. DOX-induced oxidative stress and changes of the phosphoproteome as well as epigenome were described but the exact mechanisms of the adverse long-term effects are still elusive. Here, we tested the impact of DOX treatment on cell death, oxidative stress parameters and expression profiles of proteins involved in epigenetic pathways in a cardiomyocyte cell culture model. Markers of oxidative stress, apoptosis and expression of proteins involved in epigenetic processes were assessed by immunoblotting in cultured rat myoblasts (H9c2) upon treatment with DOX (1 or 5 μM for 24 or 48 h) in adherent viable and detached apoptotic cells. The apoptosis markers cleaved caspase-3 and fractin as well as oxidative stress markers 3-nitrotyrosine and malondialdehyde were dose-dependently increased by DOX treatment. Histone deacetylases (SIRT1 and HDAC2), histone lysine demethylases (KDM3A and LSD1) and histone lysine methyltransferases (SET7 and SMYD1) were significantly regulated by DOX treatment with generation of cleaved protein fragments and posttranslational modifications. Overall, we found significant decrease in histone 3 acetylation in DOX-treated cells. DOX treatment of cultured cardiomyocyte precursor cells causes severe cell death by apoptosis associated with cellular oxidative stress. In addition, significant regulation of proteins involved in epigenetic processes and changes in global histone 3 acetylation were observed. However, the significance and clinical impact of these changes remain elusive.